The disease diabetes mellitus is characterized by metabolic defects in the production and utilization of carbohydrates that result in the failure to maintain appropriate blood sugar levels. The results of these defects include, inter alia, elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin, the hormone that regulates carbohydrate utilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most Type 2 diabetic patients are also obese.
The compounds of the invention effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
Obesity constitutes a major health risk that leads to mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost 25% of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual's mental health and self-esteem, which can ultimately affect a person's ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
The compounds, pharmaceutical compositions, and combinations of the present invention also reduce body weight, or decrease weight gain, when administered to a mammal, including a human subject. The ability of the compounds to affect weight gain is due to activation of β3 adrenergic receptors that stimulate the metabolism of adipose tissue.
β-Adrenergic agents have been generally classified into β1, β2, and β3 receptor-specific subtypes. Agonists of β-receptors promote the activation of adenyl cyclase. Activation of β1 receptors invokes an increase in heart rate while activation of β2 receptors induces smooth muscle tissue relaxation that produces a drop in blood pressure and the onset of skeletal muscle tremors. Activation of β3 receptors is known to stimulate lipolysis (e.g., the breakdown of adipose tissue triglycerides into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the loss of fat mass. Accordingly, compounds that stimulate β3 receptors are therefore useful as anti-obesity agents, and can be further used to increase the content of lean meat in edible animals. In addition, compounds that are β3 receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is presently unknown.
Until recently, β3 adrenergic receptors were believed to be located predominantly in adipose tissue, however, such β3 receptors are now known to be present in such diverse tissues as the intestine, (J. Clin. Invest., 91, 344 (1993)) and the brain (Eur. J. Pharm., 219, 193 (1992)). Stimulation of β3 receptors has also been demonstrated to induce relaxation of smooth muscle in the colon, trachea, and bronchi. See, for example, Life Sciences, 44, 1411 (1989), Br. J. Pharm., 112, 55 (1994), and Br. J. Pharmacol., 110, 1311 (1993). Furthermore, stimulation of β3 receptors has also been found to induce relaxation of histamine-contracted guinea pig ileum. See, for example, J. Pharm. Exp. Ther., 260, 1, 192 (1992).
The β3 receptor is also expressed in the human prostate (J. Clin. Invest., 91, 344 (1993). Because stimulation of the β3 receptor causes relaxation of smooth muscles that have been shown to express the β3 receptor, i.e. intestinal smooth muscle, one of ordinary skill in the art would also predict relaxation of prostate smooth muscle. Therefore, β3 agonists are useful in the treatment or prevention of prostate disease.
U.S. Pat. No. 5,977,124 discloses certain β3 adrenergic receptor agonists that may be used in the treatment of, inter alia, hypoglycemia and obesity.
U.S. Pat. No. 5,776,983 discloses certain catecholamines as β3-agonists.
U.S. Pat. No. 5,030,640 discloses certain α-heterocyclic ethanol amino alkyl indoles that may be used as growth promoters, bronchodilators, anti-depressants, and anti-obesity agents.
U.S. Pat. No. 5,019,578 discloses certain α-heterocyclic ethanolamines that may be used as growth promoters.
U.S. Pat. No. 4,478,849 discloses pharmaceutical compositions comprising certain ethanolamine derivatives and methods of using such compositions in the treatment of obesity and/or hyperglycaemia.
U.S. Pat. No. 4,358,455 discloses certain heterocyclic compounds that may be used for treating glaucoma and cardiovascular disease.
U.S. Pat. No. 5,393,779 (EP 516 349 B1) discloses certain 2-hydroxyphenethyl amines that may be used as anti-obesity and hypoglycemic agents, as well as, other related utilities.
U.S. Pat. No. 5,153,210 discloses certain heterocyclic compounds that may be used as anti-obesity and anti-hyperglycaemic agents.
U.S. Pat. No. 6,251,925 discloses biaryl compounds that may be used for the treatment of diseases susceptible to amelioration by administration of an atypical beta-adrenoceptor agonist.
U.S. Publication No. 2002-0052392A1 (PCT Publication No. WO 02/32897) discloses certain heterocyclic β3-adrenergic receptor agonists that may be used in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders, and in increasing the content of lean meat in edible animals.